GABAergic Mechanisms of Comorbid Alcohol and Nicotine Dependence

描述（由申请人提供）：酒精依赖和吸烟密切相关，但检查潜在神经化学的研究很少。对于人类来说，吸烟似乎可以在酒精依赖恢复过程中调节 GABAA-BZR 的可用性。临床数据表明，在急性戒断期间，酒精依赖的非吸烟者中 GABAA-BZR 的可用性增加，而酒精依赖的吸烟者的可用性则受到抑制。此外，长时间戒酒期间，GABAA-BZR 的可用性似乎会降低；但这尚未得到系统研究。该项目的目的是使用 [123I]iomazenil 和单光子发射计算机断层扫描 (SPECT) 确定长期口服乙醇戒断与长期同时服用乙醇和尼古丁对大脑中 GABAA-BZR 的影响。我们还将检查同时戒断乙醇和尼古丁期间 GABAA-BZR 可用性的变化，以及在持续尼古丁暴露的情况下戒断乙醇的情况，同时戒烟和戒酒与戒烟同时继续吸烟的人类中 GABAA-BZR 的模型变化。我们将对 50 只青春期动物进行扫描（每组 n=10）。所有动物将在基线时接受 2 次扫描，例如重测。第 1 组将自行长期服用乙醇 24 周，并在停药第 1 天、8 天和 12 周时进行成像。第 2 组将自行服用慢性尼古丁 24 周，并在戒断第 1 天、8 天和 12 周时进行成像。第 3A 组将自我施用乙醇加尼古丁 24 周，并将在停止乙醇和尼古丁后第 1 天、第 8 天和第 12 周进行扫描。 3B组将自行施用乙醇加尼古丁24周，并将在戒断乙醇第1天、8天和12周时进行成像，但在此戒断期间将继续自行施用尼古丁。第 4 组（对照组）将自行施用糖精 24 周，并在糖精终止后第 1 天、8 天和 12 周进行成像。将进行 MRI 扫描来追踪大脑灰质、白质以及脑脊液 (CSF) 的变化。我们假设：1）在急性乙醇戒断期间，与基线和对照相比，GABAA-BZR 可用性增加，在 12 周乙醇戒断时，与基线和对照相比，GABAA-BZR 可用性降低； 2) 尼古丁戒断期间，与基线或对照相比，GABAA-BZR 可用性没有变化； 3)与单独的乙醇相比，乙醇和尼古丁的组合将导致GABAA-BZR可用性降低，即，尼古丁将抑制乙醇诱导的增加，并且与同时从乙醇和尼古丁戒断相比，从乙醇戒断到尼古丁存在将导致更大程度地抑制增加的GABAA-BZR可用性。这项研究的结果将增进对酒精和尼古丁依赖高共病背后的神经化学机制的理解，并将对吸烟者和非吸烟者酒精依赖的治疗产生直接的临床意义。公共健康相关性：拟议的实验将通过描述大脑机制（GABAA-苯二氮卓受体）来直接影响公共健康，该机制参与酒精依赖的恢复以及酒精依赖和吸烟的相互作用。这些研究将检查酒精和尼古丁的戒断情况，以确定这些药物对大脑化学物质的相互作用。这些研究最终将提供有关如何更成功地治疗这些代价高昂的成瘾的信息。

DESCRIPTION (provided by applicant): Alcohol dependence and tobacco smoking are highly associated, yet studies examining the underlying neurochemistry are scarce. In humans, tobacco smoking appears to regulate the availability of the GABAA- BZR during the recovery from alcohol dependence. Clinical data suggest increased GABAA-BZR availability in alcohol dependent nonsmokers during acute withdrawal that is suppressed in alcohol dependent smokers. Additionally, there appears to be decreased GABAA-BZR availability during prolonged alcohol withdrawal; yet this has not been systematically studied. The purpose of this project is to determine the effects of withdrawal from chronic orally-delivered ethanol versus chronic co-administration of ethanol and nicotine on the GABAA- BZR in brain over time using [123I]iomazenil and single photon emission computed tomography (SPECT). We will also examine changes in GABAA-BZR availability during withdrawal from both ethanol and nicotine simultaneously, versus withdrawal from ethanol in the presence of continued nicotine exposure to model changes in GABAA-BZR in humans that quit drinking and smoking simultaneously vs. quitting drinking while continuing to smoke. We will obtain scans in 50 adolescent animals (n=10 per group). All animals will receive 2 scans at baseline, e.g., test-retest. Group 1 will self-administer chronic ethanol for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 2 will self-administer chronic nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 3A will self-administer ethanol plus nicotine for 24 weeks and will be scanned at 1 day, 8 days and 12 weeks withdrawal from both ethanol and nicotine. Group 3B will self-administer ethanol plus nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal from ethanol, but will continue to self-administer nicotine during this withdrawal period. Group 4, a control condition, will self-administer saccharin for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks after termination of saccharin. MRI scans will be obtained to track changes in brain gray and white matter and cerebrospinal fluid (CSF). We hypothesize that there will be 1) increased GABAA-BZR availability compared to baseline and controls during acute ethanol withdrawal and decreased GABAA-BZR availability compared to baseline and controls at 12 weeks ethanol withdrawal; 2) no change in GABAA-BZR availability compared to baseline or controls during nicotine withdrawal; and, 3) the combination of ethanol and nicotine will result in decreased GABAA-BZR availability compared to ethanol alone, i.e., nicotine will suppress the ethanol-induced increase, and withdrawal from ethanol into the presence of nicotine will result in a greater suppression of increased GABAA-BZR availability compared to withdrawal from ethanol and nicotine simultaneously. The findings from this study will advance the understanding of the neurochemical mechanisms that underlie the high comorbidity of alcohol and nicotine dependence and will have direct clinical implications for the treatment of alcohol dependence in both smokers and nonsmokers. PUBLIC HEALTH RELEVANCE: The proposed experiments will directly impact public health by delineating a brain mechanism, the GABAA- benzodiazepine receptor, which is involved in the recovery from alcohol dependence and in the interaction of alcohol dependence and tobacco smoking. These studies will examine the withdrawal from both alcohol and nicotine to determine the interaction of these drugs on brain chemistry. These studies will ultimately provide information on how to more successfully treat these costly addictions.